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Background and Aims: Sequential therapy with molecular-targeted agents (MTAs) is considered effective for unresectable hepatocellular carcinoma (HCC) patients. This study purposed to evaluate the efficacy of sequential therapy with sorafenib (SORA) as a first-line therapy and to investigate the therapeutic impact of SORA in nonalcoholic fatty liver disease (NAFLD) or nonalcoholic steato hepatitis (NASH)-related HCC., Methods: We evaluated 504 HCC patients treated with SORA (Study-1). The times of administration for sorafenib from 2009 to 2015, 2016 to 2017, and 2018 and later were defined as the early-, mid-, and late-term periods, respectively. Among them, 180 HCC patients treated with SORA in addition to MTAs in the mid- and late-term periods were divided into groups based on disease etiology (NAFLD or NASH [n = 37] and viral or alcohol [n = 143]), and outcomes were compared after inverse probability weighting (IPW) (Study-2)., Results: Overall survival (OS) of HCC patients who received sequential MTA therapy after first-line SORA was significantly longer. The median survival times (MST) were 12.6 versus 17.6 versus 17.4 months in the early-term group, mid-term group, and the later-time group (early vs. mid, p = 0.014, early vs. later. p = 0.045), respectively. (Study-1). In Study-2, there was no significant differences in OS between the Virus/alcohol group and the NAFLD/NASH group in patients who received sequential therapy (MST was 23.4 and 27.0 months p = 0.173, respectively). The NAFLD or NASH, female sex, albumin-bilirubin (ALBI) grade 2b, and major Vp (Vp3/Vp4) were significant factors for OS treated with SORA., Conclusions: Sequential therapy with SORA as the first-line treatment improved the prognosis of unresectable HCC patients and was effective regardless of HCC etiology., (© 2021 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Objective: This trial compared the efficacy and safety of transarterial chemoembolisation (TACE) plus sorafenib with TACE alone using a newly established TACE-specific endpoint and pre-treatment of sorafenib before initial TACE., Design: Patients with unresectable hepatocellular carcinoma (HCC) were randomised to TACE plus sorafenib (n=80) or TACE alone (n=76). Patients in the combination group received sorafenib 400 mg once daily for 2-3 weeks before TACE, followed by 800 mg once daily during on-demand conventional TACE sessions until time to untreatable (unTACEable) progression (TTUP), defined as untreatable tumour progression, transient deterioration to Child-Pugh C or appearance of vascular invasion/extrahepatic spread. Co-primary endpoints were progression-free survival (PFS), which is not a conventional one but defined as TTUP, or time to any cause of death plus overall survival (OS). Multiplicity was adjusted by gatekeeping hierarchical testing., Results: Median PFS was significantly longer in the TACE plus sorafenib than in the TACE alone group (25.2 vs 13.5 months; p=0.006). OS was not analysed because only 73.6% of OS events were reached. Median TTUP (26.7 vs 20.6 months; p=0.02) was also significantly longer in the TACE plus sorafenib group. OS at 1 year and 2 years in TACE plus sorafenib group and TACE alone group were 96.2% and 82.7% and 77.2% and 64.6%, respectively. There were no unexpected toxicities., Conclusion: TACE plus sorafenib significantly improved PFS over TACE alone in patients with unresectable HCC. Adverse events were consistent with those of previous TACE combination trials., Trial Registration Number: NCT01217034., Competing Interests: Competing interests: KM: Honoraria from Bayer, Eisai, MSD, Ajinomoto. Consulting or advisory role for Kowa, MSD, BMS, Bayer, Chugai, Taiho. Research funding from Chugai, Otuka, Takeda, Taiho, Sumitomo Dainippon, Daiichi Sankyo, MSD, Eisai, Bayer, Abbvie. IM: Honoraria from Novartis Pharma, Bayer Yakuhin, Bristol-Myers Squibb, Abbott Japan, Eisai, Taiho Pharmaceutical, Eli Lilly Japan, Daiichi-Sankyo, Yakult, Otsuka Pharmaceutical, Nobelpharma, EA Pharma, Teijin Pharma. Consulting or advisory role for Nano Carrier, Bayer Yakuhin, Eisai, Kyowa Hakko Kirin, Novartis Pharma, Shire, MSD, Bristol Myers Sqiibb, Eli Lilly Japan, Sumitomo Dainippon, Daiichi-Sankyo, Teijin Pharma, Takara Bio. Research funding from Bayer Yakuhin, Kyowa Hakko Kirin, Yakult, Taiho Pharmaceutical, Eli Lilly Japan, Ono Pharmaceutical, Eisai, AstraZeneca, Zeria Pharmaceutical, Chugai, Bristol Myers Sqiibb, Merck Serono, Kowa, Nano Carrier, ASLAN, Daiichi-Sankyo., Sumitomo Dainippon, Novartis Pharma, Baxalta, Boehringer Ingelheim, Takara Bio. Board membership: ASLAN, Chugai. IN: Honoraria from Bayer, Gilead, Abbvie, Otuka. IN: Research funding from Abbvie GK. HK: Honoraria from MSD, Abbvie, Bristrol-Myers Squibb, Dainippon Sumitomo and Otsuka, Research funding from Gilead, Bristrol-Myers Squibb, MSD. IA: Honoraria from AbbVie GK, Bristol Myers Squibb, Gilead, Eisai. Research funding from AbbVie GK, Otsuka, MSD, Chugai, Eisai, Astellas, Takeda. KN: Research funding from Abbvie GK.Nakao K: Honoraria from Gilead. YO: Research funding from AstraZeneca, Asteras, Ajinomoto, AsahiKasei-Kurare Medical, Bayer Yakuhin, Bristol Myers Sqiibb, Chugai, Daiichi-Sankyo, Eisai, Kyowa Hakko Kirin, Kowa, Nihon Kayaku, MSD, Otsuka, Ono, Taiho, Tanabe-Mitsubishi, Takeda, Torii, Tsumura, Zeria. YK: Honoraria from Chugai, Eli Lilly, Taiho, Nippon Shinyaku. OT: Honoraria from Novartis, Taiho, Eli Lilly, Dainippon Sumitomo, Bayer, Yakult, FUJIFILM, AstraZeneca, Ono Pharmaceutical, EA Pharma, Nippon Chemiphar, Celgene, Chugai, Bristol Myers, Eisai, Pfizer, Teijin, Daiichi Sankyo, MSD, Shire, AbbVie, Takeda. Consulting or advisory role for Eli Lilly, Dainippon Sumitomo, Taiho, Zeria Pharmaceutical, Daiichi Sankyo, Bristol Myers. Research Funding from Eli Lilly, Eisai, Novartis, Yakult Honsha, Taiho, Kowa, Kyowa Hakko Kirin, Merck Serono, Ono Pharmaceutical, Bayer, Pfizer Japan, AstraZeneca, Dainippon Sumitomo, Chugai, Bristol Myers, Zeria Pharmaceutical. KN: Honoraria from Eisai. AY: Royalties from Sumitomo Bakelite. Research funding from Canon Medical Systems, Taiho Pharmaceutical, Eisai. Honoraria from Merit Medical Systems., Fuji Pharma, Terumo International Systems, Nippon Kayaku, Canon Medical Systems, Bristol Meyer Squibb, Sumitomo Bakelite, Bayer Pharmaceuticals, Boston Scientific Japan, Taiho Pharmaceutical, Guerbet Japan, Guerbet Asia Pacific., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Sorafenib, an oral multikinase inhibitor, is approved for advanced hepatocellular carcinoma (HCC) treatment. However, its therapeutic effect in advanced HCC patients with extrahepatic metastasis remains uncertain. This study aimed to prospectively assess the efficacy, safety, and survival risk factors and evaluate the prognostic impact of sorafenib treatment in advanced HCC patients with or without extrahepatic metastasis. Between May 2009 and March 2014, 312 consecutive advanced HCC patients who received sorafenib were enrolled in this study. We evaluated their characteristics and compared the clinical outcomes of those with and without extrahepatic metastasis. Of the enrolled patients, 245 (81%) received sorafenib treatment for more than 1 month, with a median duration of 3.6 months. Eighteen patients demonstrated partial response to sorafenib therapy, 127 had stable disease, and 134 had progressive disease at the first radiologic assessment. The median survival time (MST) and progression-free survival (PFS) were 10.3 and 3.6 months, respectively. Multivariate analysis identified gender, Child-Pugh class, baseline serum des-gamma-carboxy prothrombin level, and treatment duration as independent risk factors for survival. Extrahepatic metastasis was detected in 178 patients. However, the MST, PFS, and therapeutic effect were comparable between patients with and without extrahepatic metastasis. The independent risk factors for decreased overall survival in patients with extrahepatic metastasis were similar to those affecting all patients. Our results indicated that sorafenib could be administered for hepatic reserve and as long-term treatment for advanced HCC patients regardless of their extrahepatic metastasis status., (© 2015 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)